1. Field of the Invention
The invention relates generally to the calibration and maintenance of glucose analyzers. More particularly, the invention relates to the use of alternative site glucose determinations to improve algorithm development, calibration, and/or quality control of noninvasive or implantable glucose analyzers.
2. Background Information
Diabetes is a chronic disease that results in improper production and utilization of insulin, a hormone that facilitates glucose uptake into cells. While a precise cause of diabetes is unknown, genetic factors, environmental factors, and obesity appear to play roles. Diabetics have increased risk in three broad categories: cardiovascular heart disease, retinopathy, and neuropathy. Diabetics may have one or more of the following complications: heart disease and stroke, high blood pressure, kidney disease, neuropathy (nerve disease and amputations), retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and fetal complications. Diabetes is a leading cause of death and disability worldwide. Moreover, diabetes is merely one among a group of disorders of glucose metabolism that also includes impaired glucose tolerance, and hyperinsulinemia, or hypoglycemia.
Diabetes Prevalence and Trends
Diabetes is an ever more common disease. The World Health Organization (WHO) estimates that diabetes currently afflicts 154 million people worldwide. There are 54 million people with diabetes living in developed countries. The WHO estimates that the number of people with diabetes will grow to 300 million by the year 2025. In the United States, 15.7 million people or 5.9 percent of the population are estimated to have diabetes. Within the United States, the prevalence of adults diagnosed with diabetes increased by six percent in 1999 and rose by 33 percent between 1990 and 1998. This corresponds to approximately eight hundred thousand new cases every year in America. The estimated total cost to the United States economy alone exceeds $90 billion per year. Diabetes Statistics, National Institutes of Health, Publication No. 98-3926, Bethesda, Md. (November 1997).
Long-term clinical studies show that the onset of complications can be significantly reduced through proper control of blood glucose levels. The Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N Eng J of Med, 329:977–86 (1993); U.K. Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, Lancet, 352:837–853 (1998); and Y. Ohkubo, H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, M. Shichizi, Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study, Diabetes Res Clin Pract, 28:103–117 (1995).
A vital element of diabetes management is the self-monitoring of blood glucose levels by diabetics in the home environment. However, current monitoring techniques discourage regular use due to the inconvenient and painful nature of drawing blood through the skin prior to analysis. The Diabetes Control and Complication Trial Research Group, supra. As a result, noninvasive measurement of glucose has been identified as a beneficial development for the management of diabetes. Implantable glucose analyzers eventually coupled to an insulin delivery system providing an artificial pancreas are also being pursued.
Glucose Measurement History, Approaches, and Technologies
Diabetes treatment has progressed through several stages. The combined development of insulin therapy and in-home glucose determination led to a radical improvement in the lives of diabetics. Home glucose determination has also progressed through its own succession of stages. Urine tests for glucose have given way to the invasive fingerstick glucose determinations that are more accurate but somewhat painful, also presenting a possible biohazard. The development of alternative site glucose determinations has somewhat mitigated the pain aspects, but may have introduced a new difficulty as a result of temporal and spatial differences in glucose between the well perfused fingertip and the less well perfused alternative sites. Additionally, the biohazard issue remains. Current research is focusing on the development of noninvasive technologies that will totally eliminate the pain associated with glucose determination and fluid biohazard issues. Finally, considerable progress has been made in implantable or full-loop systems incorporating both glucose determination and insulin delivery that will result in the realization of an artificial pancreas. Blood glucose determination may currently be categorized into four major types:                traditional invasive;        alternative invasive;        noninvasive; and        implantable.        
Due to the wide use of these modes of measurement and somewhat loose utilization of terminology in the literature, a detailed summary of the terminology for each mode of measurement is provided here in order to clarify usage of the terms herein.
In the medical field, the term ‘invasive’ is customarily applied to surgical methods and procedures, generally involving at least some trauma or injury to the tissue, such as cutting, in order to achieve their object. However, in the glucose determination field, the term ‘invasive’ is defined relative to noninvasive. ‘Noninvasive’ clearly describes methods, invariably signal-based, in which no biological sample or fluid is taken from the body in order to perform a glucose measurement. ‘Invasive’ then means that a biological sample is collected from the body. Invasive glucose determinations may then be further broken into two separate groups. The first is a ‘traditional invasive’ method in which a blood sample is collected from the body from an artery, vein, or capillary bed in the fingertips or toes. The second is an ‘alternative invasive’ method in which a sample of blood, interstitial fluid, or biological fluid is drawn from a region other than an artery, vein, or capillary bed in the fingertips or toes.
1. Traditional Invasive Glucose Determination
There are three major categories of traditional (classic) invasive glucose determinations. The first two utilize blood drawn with a needle from an artery or vein, respectively. The third consists of capillary blood obtained via lancet from the fingertip or toes. Over the past two decades, this has become the most common method for self-monitoring of blood glucose.
Common technologies are utilized to analyze the blood collected by venous or arterial draw and finger stick approaches. Glucose analysis includes techniques such as colorimetric and enzymatic glucose analysis. The most common enzymatic based glucose analyzers utilize glucose oxidase, which catalyzes the reaction of glucose with oxygen to form gluconolactone and hydrogen peroxide as shown by equation 1, infra. Glucose determination includes techniques based upon depletion of oxygen in the sample either through the changes in sample pH, or through the formation of hydrogen peroxide. A number of colorimetric and electro-enzymatic techniques further utilize the reaction products as a starting reagent. For example, hydrogen peroxide reacts in the presence of platinum to form the hydrogen ion, oxygen, and current; any of which may be utilized indirectly to determine the glucose concentration, as in equation 2.glucose+O2→gluconolactone+H2O2  (1)H2O2→2H++O2+2e−  (2)
It is noted that a number of alternative site methodologies such as the THERASENSE FREESTYLE (THERASENSE, INC., Alameda Calif.) collect blood samples from regions other than the fingertip or toes. These technologies are not herein referred to as traditional invasive glucose meters unless the sample is drawn from the fingertip or toes despite having similar chemical analyses such as the calorimetric or enzymatic analysis described above. However, the same device utilized to collect blood via lancet from sample sites consisting of the fingertip or toe is a traditional invasive glucose analyzer.
2. Alternative Invasive Glucose Determination
There are several alternative invasive methods of determining glucose concentration. A first group of alternative invasive glucose analyzers have a number of similarities to the traditional invasive glucose analyzers. One similarity is that blood samples are acquired with a lancet. Obviously, this form of alternative invasive glucose determination while unsuitable for analysis of venous or arterial blood, may be utilized to collect capillary blood samples. A second similarity is that the blood sample is analyzed using chemical analyses that resemble the colorimetric and enzymatic analyses describe above. The primary difference, however, is that in an alternative invasive glucose determination the blood sample is not collected from the fingertip or toes. For example, according to package labeling, the THERASENSE FREESTYLE meter may be utilized to collect and analyze blood from the forearm. This is an alternative invasive glucose determination due to the location of the lancet draw. In this first group of alternative invasive methods based upon blood draws with a lancet, a primary difference between the alternative invasive and traditional invasive glucose determination is the location of the site of blood acquisition from the body. Additional differences include factors such as the gauge of the lancet, the depth of penetration of the lancet, timing issues, the volume of blood acquired, and environmental factors such as the partial pressure of oxygen, altitude, and temperature. This form of alternative invasive glucose determination includes samples collected from the palmar region, base of thumb, forearm, upper arm, head, earlobe, torso, abdominal region, thigh, calf, and plantar region.
A second group of alternative invasive glucose analyzers is distinguished by their mode of sample acquisition. This group of glucose analyzers has a common characteristic of acquiring a biological sample from the body or modifying the surface of the skin to gather a sample without utilization of a lancet for subsequent analysis. For example, a laser poration based glucose analyzer utilizes a burst or stream of photons to create a small hole in the skin surface. A sample of substantially interstitial fluid collects in the resulting hole. Subsequent analysis of the sample for glucose constitutes an alternative invasive glucose analysis, whether or not the sample was actually removed from the created hole. A second common characteristic is that a device and algorithm are utilized to determine glucose from the sample. Herein, the term alternative invasive includes techniques that analyze biosamples such as interstitial fluid, whole blood, mixtures of interstitial fluid and whole blood, and selectively sampled interstitial fluid. An example of selectively sampled interstitial fluid is collected fluid in which large or less mobile constituents are not fully represented in the resulting sample. For this second group of alternative invasive glucose analyzers sampling sites include: the hand, fingertips, palmar region, base of thumb, forearm, upper arm, head, earlobe, eye, chest, torso, abdominal region, thigh, calf, foot, plantar region, and toes. A number of methodologies exist for the collection of samples for alternative invasive measurements including:                Laser poration: In these systems, photons of one or more wavelengths are applied to skin creating a small hole in the skin barrier. This allows small volumes of interstitial fluid to become available for a number of sampling techniques;        Applied current: In these systems, a small electrical current is applied to the skin allowing interstitial fluid to permeate through the skin;        Suction: In these systems, a partial vacuum is applied to a local area on the surface of the skin. Interstitial fluid permeates the skin and is collected.        
In all of the above techniques, the analyzed sample is interstitial fluid. However, some of these same techniques can be applied to the skin in a fashion that draws blood. For example, the laser poration method can result in blood droplets. As described herein, any technique that draws biosamples from the skin without the use of a lancet on the fingertip or toes is referred to as an alternative invasive technique. In addition, it is recognized that the alternative invasive systems each use different sampling approaches that lead to different subsets of the interstitial fluid being collected. For example, large proteins might lag behind in the skin while smaller, more diffusive, elements may be preferentially sampled. This leads to samples being collected with varying analyte and interferent concentrations. Another example is that a mixture of whole blood and interstitial fluid may be collected. These techniques may be utilized in combination. For example the SOFT-TACT, also known as the SOFTSENSE (ABBOT LABORATORIES, INC. Abbot Park Ill.), applies suction to the skin followed by a lancet stick. Despite the differences in sampling, these techniques are referred to as alternative invasive techniques sampling interstitial fluid.
The literature occasionally refers to the alternative invasive technique as an alternative site glucose determination or as a minimally invasive technique. The minimally invasive nomenclature derives from the method by which the sample is collected. As described herein, the alternative site glucose determinations that draw blood or interstitial fluid, even_microliter, are considered to be alternative invasive glucose determination techniques as defined above. Examples of alternative invasive techniques include the THERASENSE FREESTYLE when not sampling fingertips or toes, the GLUCOWATCH (CYGNUS, INC., Redwood City Calif.) the ONE TOUCH ULTRA (LIFESCAN, INC., Milpitas Calif.), and equivalent technologies.
A wide range of technologies serve to analyze biosamples collected with alternative invasive techniques. The most common of these technologies are:                Conventional: With some modification, the interstitial fluid samples may be analyzed by most of the technologies utilized to determine glucose concentrations in serum, plasma, or whole blood. These include electrochemical, electroenzymatic, and colorimetric approaches. For example, the enzymatic and colorimetric approaches described above may also be used to determine the glucose concentration in interstitial fluid samples;        Spectrophotometric: A number of approaches for determining the glucose concentration in biosamples, have been developed that utilize spectrophotometric technologies. These techniques include: Raman and fluorescence, as well as techniques using light from the ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)].As used herein, the term invasive glucose analyzer encompasses both traditional invasive glucose analyzers and alternative invasive glucose analyzers.3. Noninvasive Glucose Determination        
There exist a number of noninvasive approaches for glucose determination. These approaches vary widely, but have at least two common steps. First, an apparatus is utilized to acquire a signal from the body without obtaining a biological sample. Second, an algorithm is utilized to convert this signal into a glucose determination.
One type of noninvasive glucose determination is based upon spectra. Typically, a noninvasive apparatus utilizes some form of spectroscopy to acquire the signal or spectrum from the body. Utilized spectroscopic techniques include, but are not limited to: Raman and fluorescence, as well as techniques using light from ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)]. A particular range for noninvasive glucose determination in diffuse reflectance mode is about 1100 to 2500 nm or ranges therein. K. Hazen, Glucose Determination in Biological Matrices Using Near-Infrared Spectroscopy, doctoral dissertation, University of Iowa (1995). It is important to note that these techniques are distinct from the traditional invasive and alternative invasive techniques listed above in that the sample interrogated is a portion of the human body in-situ, not a biological sample acquired from the human body.
Typically, three modes are utilized to collect noninvasive scans: transmittance, transflectance, and/or diffuse reflectance. For example the signal collected, typically consisting of light or a spectrum, may be transmitting through a region of the body such as a fingertip, diffusely reflected, or transflected. Transflected here refers to collection of the signal not at the incident point or area (diffuse reflectance), and not at the opposite side of the sample (transmittance), but rather at some point on the body between the transmitted and diffuse reflectance collection area. For example, transflected light enters the fingertip or forearm in one region and exits in another region typically 0.2 to 5 mm or more away depending on the wavelength utilized. Thus, light that is strongly absorbed by the body such as light near water absorbance maxima at 1450 or 1950 nm would need to be collected after a small radial divergence and light that is less absorbed such as light near water absorbance minima at 1300, 1600, or 2250 nm may be collected at greater radial or transflected distances from the incident photons.
Noninvasive techniques are not limited to using the fingertip as a measurement site. Alternative sites for taking noninvasive measurements include: a hand, finger, palmar region, base of thumb, forearm, volar aspect of the forearm, dorsal aspect of the forearm, upper arm, head, earlobe, eye, tongue, chest, torso, abdominal region, thigh, calf, foot, plantar region, and toe. It is important to note that noninvasive techniques do not have to be based upon spectroscopy. For example, a bioimpedence meter would be considered a noninvasive device. Within the context of the invention, any device that reads a signal from the body without penetrating the skin and collecting a biological sample is referred to as a noninvasive glucose analyzer. For example, a bioimpedence meter is a noninvasive device.
An alternative reference method is a reference determination made at a location on the body not including the fingertips and toes. An alternative reference includes both an alternative invasive measurement and an alternative site noninvasive measurement. Hence, an alternative site noninvasive measurement is a noninvasive measurement made at physiological sites excluding the fingertips and toes.
4. Implantable Sensor for Glucose Determination
There exist a number of approaches for implanting a glucose sensor into the body for glucose determination. These implantables may be utilized to collect a sample for further analysis or may acquire a reading or signal from the sample directly or indirectly. Two categories of implantable glucose analyzers exist: short-term and long-term.
As referred to herein, a device or a collection apparatus is at least a short-term implantable (as opposed to a long-term implantable) if part of the device penetrates the skin for a period of greater than 3 hours and less than one month. For example, a wick placed subcutaneously to collect a sample overnight that is removed and analyzed for glucose content representative of the interstitial fluid glucose concentration is referred to as a short term implantable. Similarly, a biosensor or electrode placed under the skin for a period of greater than three hours that reads a signal indicative of a glucose concentration or level, directly or indirectly is referred to as at least a short-term implantable device. Conversely, devices described above based upon techniques like a lancet, applied current, laser poration, or suction are referred to as either a traditional invasive or alternative invasive technique as they do not fulfill both the three hour and skin penetration parameters. As described herein, long-term implantables are distinguished from short-term implantables by having the criteria that they must both penetrate the skin and be utilized for a period of one month or longer. Long term implantables may remain in the body for many years.
Implantable glucose analyzers vary widely, but have at least several features in common. First, at least part of the device penetrates the skin. More commonly, the entire device is imbedded into the body. Second, the apparatus is utilized to acquire either a sample of the body or a signal relating directly or indirectly to the glucose concentration within the body. If the implantable device collects a sample, readings or measurements on the sample may be collected after removal from the body. Alternatively, readings or signals may be transmitted from within the body by the device or utilized for such purposes as insulin delivery while in the body. Third, an algorithm is utilized to convert the signals into readings directly or indirectly related to the glucose concentration. An implantable analyzer may read signals from one or more of a variety of body fluids or tissues including but not limited to: arterial blood, venous blood, capillary blood, interstitial fluid, and selectively sampled interstitial fluid. An implantable analyzer may also collect glucose information from skin tissue, cerebral spinal fluid, organ tissue, or through an artery or vein. For example, an implantable glucose analyzer may be placed transcutaneously, in the peritoneal cavity, in an artery, in muscle, or in an organ such as the liver or brain. The implantable glucose sensor may be one component of an artificial pancreas.
Examples of implantable glucose monitors follow. One example of a CGMS (continuous glucose monitoring system) is a group of glucose monitors based upon open-flow microperfusion. Z. Trajanowski, G. Brunner, L. Schaupp, M. Ellmerer, P. Wach, T. Pieber, P. Kotanko, F. Skrabai, Open-flow microperfusion of subcutaneous adipose tissue for on-line continuous ex vivo measurement of glucose concentration, Diabetes Care, 20:1114–1120 (1997). Another example utilizes implanted sensors that comprise biosensors and amperometric sensors. Z. Trajanowski, P. Wach, R. Gfrerer, Portable device for continuous fractionated blood sampling and continuous ex vivo blood glucose monitoring, Biosensors and Bioelectronics, 11:479–487 (1996). Another example is the MINIMED CGMS (MEDTRONIC, INC., Minneapolis Minn.).